Transcript Slide 1

Presented by
Terje R. Pedersen, M.D.
Oslo, Norway
Patients Randomized by Country
UK 187
n=187
Norway n=425
Finland n=221
Ireland n=17
Sweden n=401
292
Germany
n=292
330
Denmark n=330
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
SEAS Steering Committee
Terje R. Pedersen (Chairman)
Ingar Holme (Statistician)
Anne B. Rossebø (Coordinator)
Antero Y. Kesäniemi
Kurt Boman
Christoph Nienaber
John Chambers
Simon Ray
Kenneth Egstrup
Terje Skjærpe
Eva Gerdts
Kristian Wachtell
Christa Gohlke-Bärwolf
Ronnie Willenheimer
Nonvoting members:
Philippe Brudi (MSP)
William Malbecq (MSD statistician)
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
SEAS Study Design

Randomized

Double-blind

Placebo-controlled

Multicentre

4 weeks placebo/diet run-in

Simvastatin 40 mg + ezetimibe 10 mg or placebo

Median duration: 4.5 years
(minimum follow-up 4 years)
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
SEAS: Primary End Point
Major Cardiovascular (CV) Events:

CV death

Aortic valve replacement surgery (AVR)

CHF as a result of progression of AS

Non-fatal myocardial infarction

CABG

PCI

Hospitalized unstable angina

Non-hemorrhagic stroke
PCI = percutaneous coronary intervention
CHF= congestive heart failure
CABG = coronary-artery bypass grafting
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
SEAS: Secondary End Points
Aortic Valve Events

Aortic valve replacement

CHF as a result of progression of AS

CV death
Ischemic CV Events

CV death

Nonfatal MI

CABG

PCI

Hospitalized unstable angina

Nonhemorrhagic stroke
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Other Objectives
Echocardiography
Safety
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Patient Definition

Men and women

Age 45 - 85 years

Asymptomatic

Valvular AS:
▬
▬

Aortic valve thickening on echocardiographic
evaluation
Doppler jet velocity ≥2.5 - ≤4.0 m/sec
Normal LV systolic function
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Exclusion Criteria

Statin therapy or indication for statins

Coronary heart disease

Other important valvular disease:
▬
Significant mitral valve stenosis or regurgitation
▬
Severe or predominant aortic regurgitation
▬
Rheumatic valvular disease or AV prosthesis or
subvalvular (hypertrophic, obstructive
cardiomyopathy) or supravalvular AS

Diabetes mellitus

Other conditions precluding participation
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Baseline Characteristics
Placebo
Simvastatin +
Ezetimibe
n= 929
n= 944
Age (years)
67.4
67.7
Women (%)
38.8
38.5
SBP (mm Hg)
144
146
DBP (mm Hg)
82
82
Smoker (%)
18
20
Ex-smoker (%)
37
35
Never smoker (%)
45
45
26.8
26.9
BMI (kg/m2)
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Baseline Medications
Placebo
Simvastatin +
Ezetimibe
n= 929
n= 944
ACE inhibitors
16.0
14.7
A-II blockers
10.5
10.1
Ca antagonists
17.2
16.6
Beta-blockers
28.8
25.6
ASA
28.0
25.0
Diuretics
24.7
22.1
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Baseline Lipids and Lipoproteins
Fasting serum lipid and lipoprotein levels at baseline (n=1,873)
Concentration
(mmol/L)
Concentration
(mg/dL)
Total cholesterol
5.74
222
LDL cholesterol
3.60
139
HDL cholesterol
1.49
58
Triglycerides
1.42
126
Apolipoprotein B
-
1.31 (g/L)
Values given as mean ± SD
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Baseline Echocardiography
Mean Values
Placebo
Simvastatin +
Ezetimibe
n= 929
n= 944
Peak velocity (m/sec)
3.10
3.09
Peak gradient (mm Hg)
39.6
39.3
Mean gradient (mm Hg)
23.0
22.7
Aortic valve area (cm2)
1.27
1.29
Bicuspid valve (%)
6.3
5.0
Transaortic
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
LDL-Cholesterol
Intention-to-Treat Population
150
Placebo
Mean (mg/dL) ±SE
125
100
75
50
Ezetimibe/Simvastatin 10/40 mg
25
0
0 0.5 1
1.5 2
2.5 3
Year
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
3.5 4
4.5 5
5.5
Primary End Point MCE
Patients with first event (%)
50
Intention-to-Treat Population
Placebo
40
Hazard ratio: 0.96, P=0.591
30
Ezetimibe/Simvastatin 10/40 mg
20
10
0
0
1
No. at risk
2
3
Years in study
4
5
Ezetimibe/Simvastatin 10/40 mg 906
817
713
618
53
Placebo
791
696
586
56
884
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Second End Point: Aortic Valve Events
Patients with first event (%)
50
Intention-to-Treat Population
40
Placebo
30
Hazard ratio: 0.97, P=0.732
Ezetimibe/Simvastatin 10/40 mg
20
10
0
0
1
No. at risk
Ezetimibe/Simvastatin 10/40 mg 914
895
Placebo
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
2
3
Years in study
836
814
732
725
4
635
611
5
55
58
Aortic Valve Replacement
50
Patients with first event (%)
Intention-to-Treat Population
40
30
Placebo
Hazard ratio: 1.00, P=0.968
Ezetimibe/Simvastatin 10/40 mg
20
10
0
0
1
No. at risk
Ezetimibe/Simvastatin 10/40 mg
915
Placebo
896
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
2
3
Years in study
4
5
837
734
640
55
816
728
618
61
Peak Aortic - Jet Velocity
0.75
Change from baseline
(m/sec) mean (±SE)
0.60
Intention-to-Treat Population
Ezetimibe/Simvastatin 10/40 mg
0.45
0.30
0.15
Placebo
0.00
Year 1
Year 2
Time
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Last follow-up
Second End Point: Ischemic CV Events
Patients with first event (%)
30
Intention-to-Treat Population
Hazard ratio: 0.78, P=0.024
20
Placebo
10
Ezetimibe/Simvastatin 10/40 mg
0
0
1
No. at risk
Ezetimibe/Simvastatin 10/40 mg 917
Placebo
898
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
2
3
Years in study
4
5
867
838
823
788
769
729
76
76
Coronary Artery Bypass Grafting
30
Patients with first event (%)
Intention-to-Treat Population
Hazard ratio: 0.68, P=0.015
20
Placebo
10
Ezetimibe/Simvastatin 10/40 mg
0
0
1
2
3
Years in study
4
5
Ezetimibe/Simvastatin 10/40 mg 925
887
848
797
80
Placebo
862
819
761
80
No. at risk
909
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Clinical Adverse Events (AE)
All Patients as Treated Population
Any serious AE (SAE)
Drug discontinuation
due to SAE
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Placebo
Ezetimibe/
Simvastatin
N=929
N=943*
n
n
463
468
79
77
P=
Clinical Adverse Events
All Patients as Treated Population
Placebo
Ezetimibe/
Simvastatin
N=929
N=943
n
n
Any SAE
Drug disconuation
due to SAE
463
468
79
77
Musculoskeletal AE
Myopathy / rhabdomyolysis
181
0
165
0
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
P=
0.28
Clinical Adverse Events
All Patients as Treated Population
Placebo
Ezetimibe/
Simvastatin
N=929
N=943
n
n
Any SAE
Drug disconuation
due to SAE
463
468
79
77
Musculoskeletal AE
181
165
Myopathy / rhabdomyolysis
0
0
New cancer
65
102
Recurrent cancer, same site
5
3
Cancer (total )
70
105
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
P=
0.28
0.01
0.01
Fatal Cancer
Cumulative percentage
20
Intention-to-Treat Population
15
Hazard ratio: 1.67
P=0.05 Unadjusted
P=0.06 With Log-rank
continuity correction
10
Ezetimibe/Simvastatin 10/40 mg
n=39 (4.1%)
5
n=23 (2.5%)
Placebo
0
0
1
No. at risk
Ezetimibe/Simvastatin 10/40 mg
Placebo
930
916
2
3
Years in study
912
890
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
884
865
4
5
855
835
89
94
Incident Cancer
All Patients as Treated Population
Placebo
(N=929)
Ezetimibe/simvastatin
(N=943)
Site
n
Lip, oral pharynx, oesophagus
Stomach
Large bowel / intestine
Pancreas
Liver, gallbladder, bile ducts
Lung
Other respiratory
Skin (any)
Breast
Prostate
Kidney
Bladder
Genital
Hematological
Other/unspecified
1
1
8
1
3
10
0
8
5
13
2
7
4
5
7
n
1
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
5
9
4
2
7
1
18
8
21
2
7
4
7
12
All differences are non-significant
All-cause Mortality
Cumulative percentage
30
Intention-to-Treat Population
Hazard ratio: 1.04, P=0.799
20
Ezetimibe/Simvastatin 10/40 mg
10
Placebo
0
0
1
No. risk
2
3
Years in study
4
5
Ezetimibe/Simvastatin 10/40 mg
930
912
884
855
89
Placebo
916
890
865
835
94
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
Major CV Events - Components
ITT Population
End Points
Major CV Events
Placebo
# of Events
Ezetimibe/Simvastatin Hazard ratio (95% CI)
355
333
56
47
AVR
278
267
CHF
23
25
Nonfatal MI
26
17
CABG
100
69*
PCI
17
8
Hospitalized UAP
8
5
Nonhematological stroke 29
33
CV Death
*P=0.02 vs. placebo
0.1
1.0
Favours Ezetimibe/Simvastatin 10/40 mg
Rossebø et al. NEJM 2008;359 (Epub ahead of print).
10.0
Favours Placebo